SUMMARY/ABSTRACT The primary mediators of beta cell destruction in Type 1 diabetes (T1D) are CD4+ and CD8+ T cells. Currently, there is a need for strategies that effectively suppress established beta cell-specific T cell reactivity in diabetics in order to reverse T1D, and rescue residual beta cell mass. The current proposal investigates the use of CD4 and CD8 co-receptor blockade to suppress ongoing beta cell autoimmunity in diabetic NOD mice. For this purpose, the nondepleting anti-CD4 and -CD8 monoclonal antibodies YTS177.9 and YTS105, respectively, will be employed. Preliminary data demonstrate that application of a short course of YTS177.9 and YTS105 results in reversal of hyperglycemia and long-term remission in recent onset diabetic NOD mice. As expected, both YTS177.9 and YTS105 have direct effects on beta cell-specific CD4+ and CD8+ T cell reactivity. Surprisingly, YTS105 also mediates protection via a mechanism involving CD11c+CD8a+ dendritic cells that indirectly affects CD4+ and CD8+ T cell pathogenicity. Herein, we propose to further investigate the novel and robust effects of YTS177.9 and YTS105 in suppressing established beta cell autoimmunity in diabetic NOD mice. Specific Aim 1 will focus on defining at the cellular level mechanisms by which YTS177.9 and YTS105 directly and indirectly influence beta cell-specific T cell reactivity. Specific Aim 2 will identify the key events driving diabetes remission in recent onset diabetic mice.